This field of art to which this invention pertains is hydrophobic filters and more particularly apparatuses and methods for testing hydrophobic filters.
Fermentation is an important process in the pharmaceutical industry that is used to make a variety of products such as hormones, enzymes, amino acids, antibiotics, and blood substitutes. The most commonly used organisms for manufacturing pharmaceutical products by fermentation are bacteria, fungi, and mammalian cells. During the manufacturing process it is important to keep contaminating organisms from being introduced into the fermentation system. For this reason, fluids that come in contact with the fermentation broth are sterilized. However, maintaining sterility is a challenge because an industrial fermentation can last up to twenty-one days. Air is typically used in the fermentation process (e.g.,for agitation, for transferring liquid to or from the fermentor and for sparging the fermentor to ensure an adequate oxygen supply) and thus, the air distribution system is a well-recognized way of introducing microbial contaminants to the fermentation system.
Recently microporous filter (membrane) cartridges have been used to provide a safe and reliable method of removing contaminants. Membrane filters are screen filters that retain particles by sieving and adsorption or size exclusion. Typically micropous membranes used in sterilizing applications will exclude particles as small as 0.1 .mu.m to 0.5 .mu.m based upon the actual membrane selected. Most sterilizing applications use 0.2 .mu.m rated membranes. There are generally two types of microporous cartridge filters, hydrophilic filters and hydrophobic filters. Hydrophilic filters are typically made from cellulose, modified polyvinylidene fluoride or nylon and are generally used in aqueous liquid filtration. In contrast, hydrophobic filters are generally used in gas filtration and liquid solvent applications. Typical hydrophobic membrane materials include polyvinylidene fluoride and polytetrafluoroethylene. The microporous membranes used in fermentation applications are manufactured from inert polymers that are cast in continuous sheets. The membrane manufacturing process is tightly controlled to give defined retention, high porosity, and reproducible porosymmetric profiles.
It is important that membrane filter cartridges provide reliable particle removal and longevity while withstanding the stresses that accompany production (e.g., heat sterilization cycles). The use of membrane filters in critical applications, those where retention characteristics must be ensured prior to actual use, requires that the integrity of the membrane be tested prior to implementation in the respective process. This requirement necessitates the use of a nondestructive integrity test. The integrity of hydrophobic membrane filters and their ability to retain bacteria, has been correlated to a solvent based nondestructive integrity test. Current test methods use solvents to wet the membranes in order to conduct integrity tests on the hydrophobic filters (e.g., bubble point and diffusion integrity tests). However solvent based integrity tests make it difficult to test in situ following sterilization of the filters because of the risk of downstream solvent contamination, the addition of an expensive solvent drying (i.e. removal) step and precautions needed for safe handling of solvents. Clearly, it is desirable to be able to test, in situ, the filters subsequent to sterilization to provide absolute assurance that the filter and/or filter housing has not lost its integrity during the sterilization process.
An alternative test methodology, the water pressure integrity test, allows for the in situ, post sterilization test of hydrophobic filters. The water integrity test is based on the capillary depression of non-wetting liquids on the outer surface of membranes. By their nature, hydrophobic membranes resist wetting by water. However, water repellent forces may be overcome by applying sufficient pressure to force water into the pores and wet out the membrane. The magnitude of the pressure can be inversely correlated to the pore size of the membrane (as the pore size decreases the pressure required increases). The water pressure integrity test measures the rate of water uptake of the hydrophobic filter and this rate has been directly correlated to the retention of bacterial challenges.
Typically water pressure integrity tests are conducted by flooding the filter housing with water under pressure. Any measured pressure drop is proportional to the rate of water permeation. However, these conventional water pressure integrity tests are all adversely affected by pressure leaks in system valving and piping, These leaks mask true test values and cause "false test failures", and/or inconclusive integrity test results. In any industrial application, process valve leaks, flange leaks or other system component leaks are inevitable. It is not a trivial task to ensure that all components are free of leaks, nor is it practical to assume that a system can be maintained to achieve this.
Thus, there is a continuing search in the field of hydrophobic filters for methods for assuring the integrity of such filters.